Hypoglycaemia

Endocrinology for FRACP

Michele O’Connell

Overview

Normal Physiology – adaptation to fastingClinical features AetiologyE l ti d tEvaluation and management

Normal perinatal physiology

Transition from environment with continuous source of glucose (maternal blood) to one where glucose is in limited and intermittent supply!Glucose is preferred substrate for brainGlucose is preferred substrate for brain metabolism, which uses most of the 5-8mcg/kg/min produced and used by full-term neonateGlucose entry into brain cells is dependent on circulating arterial glucose concentration

Elaborate defense mechanism against hypoglycaemiaSeveral metabolic systems act to maintain normoglycaemia during fasting

Integrated by ANS and hormones

Fasting adaptation

Act synergistically to enhance glucose production while simultaneously limiting peripheral glucose use

Hypoglycaemia results from:a failure one of these fasting systems, oran abnormality in a hormone that controls these systems

Mechanisms of fasting adaptation Hormonal control of fastingGLUCAGON stimulates glycogenolysis and to lesser extent gluconeogenesis & ketogenesisGH stimulates lipolysisCORTISOL stimulates gluconeogenesis (and lipolysis)lipolysis)EPINEPHRINE stimulates glycogenolysis, gluconeogenesis, lipolysis and ketogenesis

INSULIN inhibits / suppresses all of the fasting systems

Defects in glycogenolysis – glycogen storage disease (GSD)Defects in gluconeogenesis (GNG)Fatty acid oxidation disorders and defects in

Hypoglycaemia can result from…

GSD

Defects of GNGFatty acid oxidation disorders and defects in

ketogenesisCounterregulatory hormone defectsOther IEM

of GNG

FAO Defects

Counter-regulatory hormone abnormalities

Starvation response

Starvation response Starvation response

Starvation response•GH, cortisol and epineph levels also ↑

Symptoms and signs of hypoglycaemia

Pointers to diagnosis

Neonatal

JitterinessLethargy, poor feeding

Postnatal

HeadacheIrritability

SeizuresHypothermiaResp distress / Apnoea

Syncope / collapseConfusionSeizures

Definition of hypoglycaemia

Blood glucose level <2.6mmol/lSymptoms of hypoglycaemiaResolution of symptoms with treatment to raise BGLBGL

Capillary glucometer readings are unreliable at low readings

Confirm with true lab glucose before ‘critical sample’

AetiologyTransient neonatal hypoglycaemia

Persistent hypoglycaemianeonatal, infancy or childhood

Transient Neonatal HypoglycaemiaDay 1:

Normal newborn – developmental immaturityDay 2:

Hyperinsulinism due to maternal factors – eg DM, iv glucose in labour

M l dMore prolonged:PrematuritySGA, discordant twin, birth asphyxia, maternal PET

Depleted stores and hyperinsulinismBeckwith Wiedemann syndrome

Other:Increased utilization: sepsis, fever

Persistent HypoglycaemiaHyperinsulinismD/o of glycogenolysis

GSD 3, 6, 9, 0D/o of gluconeogenesis

GSD 1a 1bGSD 1a, 1b, Fructose 1,6-diphosphatase def, pyruvate carboxylase def

FAO defectsCounter-regulatory hormone deficiencyGalactosemia

Common age-related presentations

Neonatal

PretermSGA

Postnatal and beyond…

HyperinsulinismGSD

Infant of diabetic mumHyperinsulinismHypopituitarism

Ketotic hypoglycaemiaHypopituitarism

The shorter the fasting interval before hypoglycaemia manifests, the more severe the defect

HyperinsulinismImportant to recogniseInsulin suppresses all mechanisms of fuel generation↓glucose, ↓gluconeogenesis, ↓FAO & ↓ketogenesisketogenesisUnique combination of hypoglycaemia + suppression of ketogenesis → no fuel source for brainANY detectable insulin (>2microU/ml) in the presence of a BGL <2.6mmol/l is inappropriate Aim of treatment is BGL >4.0mmol/l

Insulin secretion - mechanism

The beta cell functions to transform the chemical energy of glucose metabolism (ATP) to electrical energy that governs insulin secretion by way of voltage-gated calcium channels g gProcess regulated by KATP channels, which consist of an inward rectifying channel of the Kir6.2 family and its regulatory subunit, the sulphonyurea receptor SUR1.

Persistent Hyperinsulinaemic Hypoglycaemia of Infancy (PHHI)

Clinically and genetically heterogenous disorders which result in dysregulated insulin secretion and severe and persistent hypoglycaemiaCan be caused by alterations in the structural, functional, or regulatory components of the KATP channelThese alterations include:

mutations in SUR1mutations in Kir6.2Glutamate dehydrogenase gene mutations Glucokinase gene mutations

Also associated with:SCHAD deficiency (exceptionally rare)Congenital disorders of glycosylation

Loss of function mutations in

genes encoding Kir6.2 / SUR 1 (KATP channel stays closed)

Activating mutation of GK

gene

Mutations in genes that alter

ATP:ADP ratio eg GDH

KATP channel HI

Loss of function mutations in either Kir6.2 or SUR1 subunits Most common and most severe form of PHHI>100 known mutations in gene for SUR1>100 known mutations in gene for SUR1 (ABCC8); ~20 in gene for Kir6.2 (KCNJ11)

Can be AR, AD or sporadic AR inheritance forms tend to be more severe

Histologic forms of sporadic KATP -HI

Focal (40-60%)Distinct nodular proliferation of tissue within an otherwise normal pancreas“Double hit” mechanism

i) loss of maternal allele in p15 region of Chr11Ii) i i h l ll l h i b l d bIi) mutation in the paternal allele, that is now unbalanced by normal maternal allele

→Somatic reduction to hemizygosity, or homozygosity for mutated paternal allele in a portion of beta cells

→ focal abnormal lesionDiffuse

Beta cells throughout the pancreas are abnormalMuch more difficult to manage

Glutamate dehydrogenase HI2nd most common HIGain of function mutation of GDH

Key regulator of amino acid and NH3 metabolism in pancreatic beta cells, liver and brain

‘Hyperinsulinism & hyperammonaemia syndrome’yp yp yGDH is normally activated by leucine

Leucine sensitivity is a hallmark (protein meal)Fasting and postprandial hypoglycaemia

Usually less severe than KATP-HIOften present at few months of ageNH3 usually x2-3 normal; asymptomatic

Glucokinase HI

Activating mutations in GCK which encodes glucokinaseIncreased affinity of glucokinase for glucose, leads to dysregulated insulin productionleads to dysregulated insulin production

Pointers to HI

Macrosomic baby (or SGA / asphyxia)Early onset hypoglycaemia – often severe, recurrent Glucose requirement usually >10mg/kg/minq y g gGlycaemic response to glucagon

Investigations:Detectable insulin at hypoglycaemiaAbsence of ketones (bld and urine)Inappropriately low FFA

Counter-regulatory hormone defects

Deficiencies of ACTH / cortisol or GH

Hypoglycaemia in GHD is due to decreased lipolysis (and glycogenolysis to lesser extent)p y ( g y g y )

In ACTH/ cortisol deficiency, hypoglycaemia results from increased insulin sensitivity, decreased gluconeogenesis and increased glucose oxidation

Congenital HypopituitarismMay have associated cerebral or midline abnormalitiesSepto-optic dysplasiaMicropenis in boys with GH deficiencySome forms related to transcription factor mutations –PROP1, SOX2, SOX3, LHX3, LHX4

Acquired hypopituitarismPost infectious haemorrhagePost infectious, haemorrhageOlder children – post surgery / radiation, infiltration

Primary adrenal insufficiencyNewborn: CAH, congenital adrenal hypoplasiaOlder child: Addison’s, ADL, TB, haemorrhage etc

Defects in glycogenolysis

Glycogen storage disorders (GSD) due to AR mutations in genes involved in glycogenolysisHepatomegaly (soft; often massive)Hypoglycaemia with fastingHypoglycaemia with fasting

Usually present in later infancy as inter-feed interval increases, or during intercurrent illness

Lipolysis and ketogenesis intact Less symptomatic than HI as alternate fuel availableIncreased TG and ketone levels

GSD 0 – glycogen synthase deficiency

GSD IX

GSD 1a; GSD 1b mutn in G6P transporter

GSD III

GSD VICommon

step in GNG

GSD

GSD 1a – impairment of both glycogenolysis and GNG; early hypoglycaemia can occur

GNG defect causes lactic acidosisCompletely dependent on exogenous glucoseKidney involvement; RTA, microalbuminuriay

GSD IIIa/w muscle weakness, cardiomyopathy, hypotonia

GSD VI and IX – milder phenotypesGSD 0: defect in glycogen synthesis

fasting hypoglycaemia and postprandial hyperglycaemiaCHO – lipolysis in liver – elevated lactate

Defects of gluconeogenesis

Fructose 1,6-diphosphatase deficiencyPhosphoenolpyruvate carboxykinase (PEPCK) deficiencyPyruvate kinase deficiency

F tFeatures:Glycogenolysis remains intactLater onset: hypoglycaemia occurs in setting of fasting or intercurrent illnessPositive glucagon response in the fed but not fasted state Keto- and lactic acidosis; hyperuricemia, hyperlipidemiaHepatomegaly (lipid as opposed to glycogen storage)

Fatty acid oxidation defectsErrors in pathway of :

fatty acid uptake & activation and mitochondrial oxidation

Defects in:Carnitine synthesis, CPT1 and 2 (transporters)AcetylCoA dehydrogenase SCAD MCAD LCADAcetylCoA dehydrogenase – SCAD, MCAD, LCADHMG-CoA (3 hydroxy-3methylglutaryl CoA) lyase

Delayed onset (after infancy)Phenotype varies according to level of mutation

Often unmasked by fasting / intercurrent illnessSkeletal and cardiac muscle and liver – target organs

Features of FAO defects

Clinical:Myopathy, cardiomyopathyEncephalopathy (Reye like syndrome)Hepatic failureHepatic failure

Laboratory:Low or absent ketonesDiagnosis – urinary organic acids, carnitine profiles

Rarer causes…Galactosemia (GALT def)

Clinical features:Neonatal onsetpost-prandial hypoglycaemiaNeonatal cholestasis,

Hereditary Fructose Intolerance

Clinical features:Onset after weaningDeficiency of fructose 1-phosphate aldolase (inhibits ,

diarrhoea

Lab features:Non-ketoticUrine reducing substance +Increased Galactose-1-PLow Galacotse 1 phosphate uridyl transferase (GALT) level

hepatic GNG)RTA, cholestasis, failure to thrive

Lab features:Non-ketoticUrine reducing substance +Hypo after fructose load

Accelerated starvation

Previously / often referred to as ‘ketotic hypoglycaemia’, but preferable not to use that termCommonest cause of hypoglycaemia beyond infancyImpaired fasting adaptation

Clinical Features:Often lean childEarly morning hypoglycaemiaHypoglycaemia following prolonged fast (eg intercurrent illness) Usually onset age 2-5 years; resolves by 10 years Diagnosis of exclusion

Evaluation and Management

See additional slides for clinical history etc

(minimum - preferably >4.0mmol/l)

Additional slides…

Aetiology

Decreased stores

Ketotic hypoglycaemia / ‘accelerated starvation’

Increased utilisation

HyperinsulinismFAO defect

GSD/GNG defectGalactosaemiaFructose intolerance

Septicaemia / stress

Most common causes by age…

Accelerated starvation, Hypopituitarism